The present disclosure provides compounds of the formula: where R, R, R, R, R, A, and B are as described herein, pharmaceutically acceptable salts thereof, and methods of using these compounds and salts for treating patients for cancer.
Legal claims defining the scope of protection, as filed with the USPTO.
. The compound according to, wherein A is —OCHCH—, or a pharmaceutically acceptable salt thereof.
. The compound according to, wherein B is —C(O)—, or a pharmaceutically acceptable salt thereof.
. The compound according to, wherein Ris H or methyl, or a pharmaceutically acceptable salt thereof.
. The compound according to, wherein Ris H, F, Cl, methyl, methoxy, ethyl, isopropyl, or cyclopropyl or a pharmaceutically acceptable salt thereof.
. The compound according to, wherein R is H or F.
. The compound according to, wherein Ris H or Cl, or a pharmaceutically acceptable salt thereof.
. A pharmaceutical composition comprising a compound according to, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
. A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a pharmaceutical composition according to, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.
. A method of treating a patient for cancer, comprising administering to a patient in need thereof, an effective amount of a compound according to, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.
. The method according towherein the cancer is non-small cell lung cancer, and wherein one or more cells express KRas G12C mutant protein.
. The method according towherein the cancer is colorectal cancer, and wherein one or more cells express KRas G12C mutant protein.
. The method according towherein the cancer is pancreatic cancer, and wherein one or more cells express KRas G12C mutant protein.
. The method according towherein the patient has a cancer that was determined to have one or more cells expressing the KRas G12C mutant protein prior to administration of the compound or a pharmaceutically acceptable salt thereof.
. A method of treating a patient with a cancer that has a KRAS G12C mutation comprising administering to a patient in need thereof an effective amount of a compound according to, or a pharmaceutically acceptable salt thereof.
. The method according to, wherein the patient is also administered an effective amount of one or more of a PD-1 inhibitor, a PD-L1 inhibitor, a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof, an EGFR inhibitor, or a pharmaceutically acceptable salt thereof, an ERK inhibitor, or a pharmaceutically acceptable salt thereof, a platinum agent, and or pemetrexed, or a pharmaceutically acceptable salt thereof.
. The compound, or a pharmaceutically acceptable salt thereof, according to, for use in therapy.
. The compound, or a pharmaceutically acceptable salt thereof, according to, for use in the treatment of cancer.
. The compound, or a pharmaceutically acceptable salt thereof, for use according to, wherein the cancer is selected from the group consisting of lung cancer, pancreatic cancer, cervical cancer, esophageal cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma, and colorectal cancer.
. The compound, or a pharmaceutically acceptable salt thereof, according tofor use in simultaneous, separate or sequential combination with one or more of a PD-1 or PD-L1 inhibitor; a CDK4/CDK6 inhibitor, or a pharmaceutically acceptable salt thereof; an EGFR inhibitor, or a pharmaceutically acceptable salt thereof; an ERK inhibitor, or a pharmaceutically acceptable salt thereof; a platinum agent; and or pemetrexed, or a pharmaceutically acceptable salt thereof, in the treatment of cancer.
Complete technical specification and implementation details from the patent document.
This application is the national stage of PCT international application number PCT/US2021/060715, filed Nov. 24, 2021, this PCT international application claims the benefit of U.S. Provisional Application No. 63/121,272, filed Dec. 4, 2020, which is herein incorporated by reference in its entirety.
The present disclosure relates to novel tricyclic heterocyclic compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions including the tricyclic heterocyclic compounds and salts, and methods of using the compounds and salts to treat cancers such as lung cancer, colorectal cancer, pancreatic cancer, bladder cancer, cervical cancer, endometrial cancer, ovarian cancer, cholangiocarcinoma or esophageal cancer.
The MAPK/ERK signaling pathway relays extracellular stimuli to the nucleus, thereby regulating diverse cellular responses including cell proliferation, differentiation, and apoptosis. KRas protein is an initiator of the MAPK/ERK signaling pathway and functions as a switch responsible for inducing cell division. In its inactive state, KRas binds guanosine diphosphate (GDP), effectively sending a negative signal to suppress cell division. In response to an extracellular signal, KRas is allosterically activated allowing for nucleotide exchange of GDP for guanosine triphosphate (GTP). In its GTP-bound active state, KRas recruits and activates proteins necessary for the propagation of growth factor induced signaling, as well as other cell signaling receptors. Examples of the proteins recruited by KRas-GTP are c-Raf and PI3-kinase. KRas, as a GTP-ase, converts the bound GTP back to GDP, thereby returning itself to an inactive state, and again propagating signals to suppress cell division. KRas gain of function mutations exhibit an increased degree of GTP binding and a decreased ability to convert GTP into GDP. The result is an increased MAPK/ERK signal which promotes cancerous cell growth. Missense mutations of KRas at codon 12 are the most common mutations and markedly diminish GTPase activity.
Oncogenic KRas mutations have been identified in approximately 30% of human cancers and have been demonstrated to activate multiple downstream signaling pathways. Despite the prevalence of KRas mutations, it has been a difficult therapeutic target. (Cox, A. D.? Nat. Rev. Drug Disc. 2014, 13, 828-851; Pylayeva-Gupta, y et al.. Nat. Rev. Cancer 2011, 11, 761-774).
WO2015/054572 and WO2016/164675 disclose certain quinazoline derivatives capable of binding to KRas G12C. WO2016/044772 also discloses methods of using such quinazoline derivatives. WO2020/0081282 discloses KRas G12C inhibitors. WO2018/206539 and WO2020/178282 disclose certain heteroaryl compounds capable of binding to KRas G12C RAS proteins.
There remains a need to provide alternative, small molecule KRas inhibitors. In particular, there is a need to provide more potent, orally deliverable KRas inhibitors that are useful for treating cancer. More particularly, there is a need to provide small molecule inhibitors that specifically inhibit KRas GTP activity. There is also a need to provide small molecule KRas inhibitors that exhibit greater efficacy at the same or reduced KRas inhibitory activity. Further, there is a desire to provide KRas inhibitors that exhibit better pharmacokinetic/pharmacodynamic properties. Also, there is a need to provide more potent KRas inhibitors that exhibit increased efficacy with reduced or minimized untoward or undesired effects. The present disclosure addresses one or more of these needs by providing novel KRas inhibitors.
The present disclosure provides a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
As used herein, the term halogen means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). As used herein, the term alkyl means saturated linear or branched-chain monovalent hydrocarbon radicals. Examples of “—Calkyl” include, but are not limited to, methyl, ethyl, propyl, 1-propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. As used herein, the term “—Cheteroalkyl” means saturated linear or branched-chain monovalent hydrocarbon radicals containing one to four carbon atoms and at least one heteroatom. As used herein, the term “—Ccycloalkyl” means saturated monovalent cyclic molecules with three to six carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Regarding Rand R, the two groups may combine with the nitrogen they are attached to when chemistry allows to form a Cheterocycloalkyl. As used herein, the term “—Cheterocycloalkyl” means saturated monovalent cyclic molecules with four to five carbon atoms and at least one heteroatom. Examples of heterocycloalkyl groups include, but are not limited to, morpholine, pyrrolidine, piperidine, imidazolidine, pyrazolidine, and piperazine.
An embodiment disclosed herein provides a compound of Formula Ia
where R, R, R, R, R, A, and B are as defined above, or a pharmaceutically acceptable salt thereof.
An embodiment disclosed herein provides a compound of Formula I or Ia wherein A is —OCH—, —N(R)CH—, —OCHCH—, or —N(R)CHCH—, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula I or Ia wherein A is —OCH— or —OCHCH—, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula I or Ia wherein A is —OCHCH—, or a pharmaceutically acceptable salt thereof.
A further embodiment provides a compound of Formula I or Ia wherein B is —C(O)—, or a pharmaceutically acceptable salt thereof.
A further embodiment provides a compound of Formula I or Ia wherein Ris —CN or —C(O)C≡CR, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula I or Ia wherein Ris a group of the formula
or a pharmaceutically acceptable salt thereof.
A further embodiment provides a compound of Formula I or Ia wherein Ris H or methyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula I or Ia wherein Ris H, or a pharmaceutically acceptable salt thereof.
A further embodiment provides a compound of Formula I or Ia wherein Ris H, halogen, preferably F or Cl, methyl, methoxy, ethyl, isopropyl, or cyclopropyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula I or Ia wherein Ris halogen, preferably F or Cl, or a pharmaceutically acceptable salt thereof.
A further embodiment provides a compound of Formula I or Ia wherein Ris a group of the formula
or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula I or Ia wherein Ris a group of the formula
or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula I or Ia wherein Ris a group of the formula
or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein R is H or halogen, preferably F, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Ris H, halogen, CHF, CHF, CHOH, or CHOCH, or a pharmaceutically acceptable salt thereof. A further embodiment provides a compound of Formula I or Ia wherein Ris halogen, preferably Cl, or a pharmaceutically acceptable salt thereof.
A further embodiment provides a compound of Formula I or Ia wherein Ris H or CH, or a pharmaceutically acceptable salt thereof.
A further embodiment provides a compound of Formula I or Ia wherein Ris H, F, Cl, —CHF, —CF, or —CHOH, or a pharmaceutically acceptable salt thereof. A further embodiment provides a compound of Formula I or Ia wherein Ris H, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Ris H, —CHF, —CHF, —CHOH, —CHOCH, —CHN(CH), or —CH-morpholine, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula I or Ia wherein Ris H, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Ris H and Ris H, —CHF, —CHF, —CHOH, —CHOCH, —CHN(CH), or —CH-morpholine, or a pharmaceutically acceptable salt thereof.
Another embodiment provides a compound of Formula I or Ia wherein Ris H, F, Cl, —CHF, —CF, or —CHOH and Ris H, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Rand Rare both H, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Ris —CN or —C(O)C≡CRand Ris H, methyl, —CHF, or —CHOH, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Ris a group of the formula
and Ris H, —CHF, —CHF, —CHOH, —CHOCH, —CHN(CH), or —CH-morpholine, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Ris a group of the formula
and Ris H, F, Cl, CHF, CF, or CHOH, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Ris a group of the formula
and Rand Rare both H, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein Ris a group of the formula
and Ris tert-butyl and Ris —CN, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein A
is —OCH—, —N(R)CH—, —OCHCH—, or —N(R)CHCH—, and B is —C(O)—, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein A is —OCH— or —OCHCH— and B is —C(O)—, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein A
is —OCHCH— and B is —C(O)—, or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein A
is —OCH—, —N(R)CH—, —OCHCH—, or —N(R)CHCH—; B is C(O); and Ris H or —CH; or a pharmaceutically acceptable salt thereof.
An embodiment provides a compound of Formula I or Ia wherein A
is —OCH— or —OCHCH—; B is —C(O)—; and Ris H or methyl; or a pharmaceutically acceptable salt thereof.
Unknown
March 31, 2026
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